The present invention is broadly concerned with an improved method for treating ophthalmic diseases in veterinary animals. More particularly, it is concerned with a method for topical ophthalmic use of tacrolimus in dogs and cats.
Conjunctivitis, or inflammation of the mobile mucous membrane covering the inner surfaces of the eyelids, is common in all domestic pets. The anatomy of dogs, cats, horses, ruminants and certain other quadrupeds includes a third eyelid, located between the cornea and the lower eyelid in the nasal portion of the lower conjuctival sac. The third eyelid includes a cartilage skeleton, a seromucoid gland and a conjunctival membrane covering both the inner, bulbar and outer, palpebral surfaces. The inner conjunctival surface includes an especially high concentration of lymphocytes that form active follicles when they are stimulated by antigens. For this reason, dogs and cats are particularly subject to development of a conjunctival disorder involving follicle proliferation on the third eyelid. The gland of the third eyelid produces about 50% of the precorneal tear film, so conjunctival disease leading to substantial impairment of the function of the third eye gland can lead to chronic corneal diseases such as keratitis.
When the conjunctival disease process is caused by infection, such as by bacterial pathogens, it is treatable using a therapeutic antibiotic. Chronic superficial keratitis (CSK), chronic keratoconjunctivitis sicca (KCS) and feline eosinophilic keratoconjunctivitis (FEK) are thought to be immune-mediated. CSK is believed to be caused by immune-mediated inflammation of the cornea, exacerbated by external factors such as environmental pollution and exposure to ultraviolet light. KCS may be induced by drugs, surgery, trauma, distemper or poisoning. FEK may be a hypersensitivity reaction similar to allergic diseases in humans which causes inflammatory occlusion of lacrimal ductules. However, most cases are idiopathic, and many of these cases are thought to be associated with autoimmune lymphocyte infiltration and destruction of the gland of the third eyelid and associated reduction in the precorneal tear film.
Certain breeds of dog, such as German shepherds, greyhounds, huskies and dachshunds are particularly subject to a form of interstitial keratitis known as Uberreiter's syndrome, plasma cell conjunctivitis or plasmoma, also called “German Shepherd Pannus” affecting the third eyelid. Kelpies, Australian cattle dogs, border collies, poodle and Labrador retrievers are subject to a similar disease. While some breeds appear to be more prone to CSK, KCS and FEK, these are important diseases found in all breeds of dogs, cats and in a number of other animal species.
Failure to provide adequate and consistent management of these diseases can result in infection, impairment of vision and eventual blindness. Topical cyclosporine has been the preferred therapeutic agent for treatment of chronic KCS in dogs. Although the mechanism of action has not yet been fully elucidated, it is thought to inhibit immune responses and it is known to increase tear production. It has also been employed in the management of CSK in the dog. However, consistent administration of cyclosporine to canines is difficult, because the composition is irritating and causes a burning sensation in the eyes. Even when there is adherence to a therapeutic regimen, the drug is estimated to have an efficacy rate of only about 75-85%.
Preliminary trials of cyclosporine for management of KCS in cats have not been promising. There is some support in the literature for contraindication against treatment of FEK with cyclosporine, because of concern that cyclosporine will potentiate underlying viral keratitis.
Accordingly, there remains a need for an effective, relatively inexpensive topical therapeutic agent for the treatment of conjunctivitis of the third eyelid in dogs as well as cats and which has a relatively low incidence of negative physiological responses.